A SOX2-engineered epigenetic silencer factor represses the glioblastoma genetic program and restrains tumor development

Author:

Benedetti Valerio1ORCID,Banfi Federica12ORCID,Zaghi Mattia1ORCID,Moll-Diaz Raquel1ORCID,Massimino Luca1ORCID,Argelich Laura1ORCID,Bellini Edoardo1ORCID,Bido Simone1ORCID,Muggeo Sharon1ORCID,Ordazzo Gabriele1ORCID,Mastrototaro Giuseppina1ORCID,Moneta Matteo1,Sessa Alessandro1ORCID,Broccoli Vania12ORCID

Affiliation:

1. Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.

2. CNR Institute of Neuroscience, 20129 Milan, Italy.

Abstract

Current therapies remain unsatisfactory in preventing the recurrence of glioblastoma multiforme (GBM), which leads to poor patient survival. By rational engineering of the transcription factor SOX2, a key promoter of GBM malignancy, together with the Kruppel-associated box and DNA methyltransferase3A/L catalytic domains, we generated a synthetic repressor named SOX2 epigenetic silencer (SES), which induces the transcriptional silencing of its original targets. By doing so, SES kills both glioma cell lines and patient-derived cancer stem cells in vitro and in vivo. SES expression, through local viral delivery in mouse xenografts, induces strong regression of human tumors and survival rescue. Conversely, SES is not harmful to neurons and glia, also thanks to a minimal promoter that restricts its expression in mitotically active cells, rarely present in the brain parenchyma. Collectively, SES produces a significant silencing of a large fraction of the SOX2 transcriptional network, achieving high levels of efficacy in repressing aggressive brain tumors.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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